Congestive heart failure is a life-threatening condition in which myocardial contractility is depressed so that the heart is unable to pump adequate amounts of blood to meet the body's metabolic needs. The leading causes for heart failure are believed to be an inadequate oxygen supply to the heart muscle or cardiomyopathy, a disorder of abnormality in the heart muscle tissue. As cardiac output decreases, other neurological mechanisms are activated, causing arterial and venous constriction, the redistribution of tissue blood flow and an increase in circulatory blood volume. As the condition worsens, the patient experiences edema, increased heart size, increased myocardial wall tension, and eventually the heart stops pumping.
Drugs which increase the tone of the heart muscle are described as having positive inotropic activity and are characterized as cardiotonic agents. Digitalis glycosides have long been used to increase myocardial contractility and reverse the detrimental changes seen in congestive heart failure. More recently, dopamine, dobutamine, amrinone and milrinone have been used to provide necessary inotropic support for the failing heart.
Cardiotonic agents which are described as having positive inotropic activity include the 5-pyridyl substituted pyridones disclosed in U.S. Pat. Nos.: 4,004,012; 4,072,746; 4,107,315; 4,137,233; 4,199,586; 4,271,168; and 4,107,315; in GB 20706006A; and in PCT published Appl. No. PCT/CH81/00023. Other cardiotonic drugs include the diazacyclic substituted carbostyril compounds disclosed in U.S. Pat. Nos. 4,414,390 and 4,415,572, cardiotonic pyridyl substituted carbostyril compounds disclosed in EPO application Ser. No. 84308925.1, and the 5-phenyl-thiazole compounds disclosed in U.S. Pat. No. 4,148,070.
Cardiotonic bicyclic heteroaryl-5-substituted pyridyl compounds are disclosed in PCT published application Ser. No. PCT/US83/01285; and, cardiotonic diazaheterocyclic-5-substituted pyridyl compounds are disclosed in U.S. Pat. Nos. 4,432,979, 4,514,400 and 4,539,321. Each of the aforementioned is assigned to the same assignee as the present application.